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Characterization of the deoxyguanosine-lysine cross-link of methylglyoxal.

Petrova KV, Millsap AD, Stec DF, Rizzo CJ - Chem. Res. Toxicol. (2014)

Bottom Line: We have examined the reaction of methylglyoxal, deoxyguanosine (dGuo), and Nα-acetyllysine (AcLys) and determined the structure of the cross-link to be the N2-ethyl-1-carboxamide with the lysine side chain amino group (1).Further, the cross-link between methylglyoxal, dGuo, and a peptide (AcAVAGKAGAR) was also characterized.The mechanism of cross-link formation is likely to involve an Amadori rearrangement.

View Article: PubMed Central - PubMed

Affiliation: Departments of Chemistry and Biochemistry, Center in Molecular Toxicology, and Vanderbilt-Ingram Cancer Center, Vanderbilt University , Nashville, Tennessee 37235, United States.

ABSTRACT
Methylglyoxal is a mutagenic bis-electrophile that is produced endogenously from carbohydrate precursors. Methylglyoxal has been reported to induce DNA-protein cross-links (DPCs) in vitro and in cultured cells. Previous work suggests that these cross-links are formed between guanine and either lysine or cysteine side chains. However, the chemical nature of the methylglyoxal induced DPC have not been determined. We have examined the reaction of methylglyoxal, deoxyguanosine (dGuo), and Nα-acetyllysine (AcLys) and determined the structure of the cross-link to be the N2-ethyl-1-carboxamide with the lysine side chain amino group (1). The cross-link was identified by mass spectrometry and the structure confirmed by comparison to a synthetic sample. Further, the cross-link between methylglyoxal, dGuo, and a peptide (AcAVAGKAGAR) was also characterized. The mechanism of cross-link formation is likely to involve an Amadori rearrangement.

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Proposedstructures of the 2:1 adducts of methylglyoxal or glyoxalwith dGuo.
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fig5: Proposedstructures of the 2:1 adducts of methylglyoxal or glyoxalwith dGuo.

Mentions: Structures of the 2:1 dGuo adducts of methylglyoxal and glyoxalhave been proposed previously (5–7, Figure 5).7,42,43 The formation of the proposed 2:1 adducts are anticipatedto be reversible and therefore expected to equilibrate with dGuo orthe 1:1 adduct after isolation;7 this wasin fact shown to be the case for the 2:1 glyoxal-dGuo adduct (7).43 The 2:1 methylglyoxal adductswe observed were stable, which would seemingly rule out the previouslyproposed structures. Our data for one of the 2:1 methylglyoxal-dGuoadducts (tr 16.6 min, Figure 4C) suggested 8 (stereochemistry unknown)as the structure, and details of the NMR and mass spectrometric analyseswill be reported separately. The proposed structure is related tothe previously characterized 2:1 methylglyoxal-arginine adduct 9.44,45 We assume that the remaining2:1 adducts are diastereomers of 8 (tr 17.1 and 17.9 min, Figure 4C),although it is possible that other isomeric species are present andthat their distribution is dependent upon the reaction conditions.


Characterization of the deoxyguanosine-lysine cross-link of methylglyoxal.

Petrova KV, Millsap AD, Stec DF, Rizzo CJ - Chem. Res. Toxicol. (2014)

Proposedstructures of the 2:1 adducts of methylglyoxal or glyoxalwith dGuo.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4060920&req=5

fig5: Proposedstructures of the 2:1 adducts of methylglyoxal or glyoxalwith dGuo.
Mentions: Structures of the 2:1 dGuo adducts of methylglyoxal and glyoxalhave been proposed previously (5–7, Figure 5).7,42,43 The formation of the proposed 2:1 adducts are anticipatedto be reversible and therefore expected to equilibrate with dGuo orthe 1:1 adduct after isolation;7 this wasin fact shown to be the case for the 2:1 glyoxal-dGuo adduct (7).43 The 2:1 methylglyoxal adductswe observed were stable, which would seemingly rule out the previouslyproposed structures. Our data for one of the 2:1 methylglyoxal-dGuoadducts (tr 16.6 min, Figure 4C) suggested 8 (stereochemistry unknown)as the structure, and details of the NMR and mass spectrometric analyseswill be reported separately. The proposed structure is related tothe previously characterized 2:1 methylglyoxal-arginine adduct 9.44,45 We assume that the remaining2:1 adducts are diastereomers of 8 (tr 17.1 and 17.9 min, Figure 4C),although it is possible that other isomeric species are present andthat their distribution is dependent upon the reaction conditions.

Bottom Line: We have examined the reaction of methylglyoxal, deoxyguanosine (dGuo), and Nα-acetyllysine (AcLys) and determined the structure of the cross-link to be the N2-ethyl-1-carboxamide with the lysine side chain amino group (1).Further, the cross-link between methylglyoxal, dGuo, and a peptide (AcAVAGKAGAR) was also characterized.The mechanism of cross-link formation is likely to involve an Amadori rearrangement.

View Article: PubMed Central - PubMed

Affiliation: Departments of Chemistry and Biochemistry, Center in Molecular Toxicology, and Vanderbilt-Ingram Cancer Center, Vanderbilt University , Nashville, Tennessee 37235, United States.

ABSTRACT
Methylglyoxal is a mutagenic bis-electrophile that is produced endogenously from carbohydrate precursors. Methylglyoxal has been reported to induce DNA-protein cross-links (DPCs) in vitro and in cultured cells. Previous work suggests that these cross-links are formed between guanine and either lysine or cysteine side chains. However, the chemical nature of the methylglyoxal induced DPC have not been determined. We have examined the reaction of methylglyoxal, deoxyguanosine (dGuo), and Nα-acetyllysine (AcLys) and determined the structure of the cross-link to be the N2-ethyl-1-carboxamide with the lysine side chain amino group (1). The cross-link was identified by mass spectrometry and the structure confirmed by comparison to a synthetic sample. Further, the cross-link between methylglyoxal, dGuo, and a peptide (AcAVAGKAGAR) was also characterized. The mechanism of cross-link formation is likely to involve an Amadori rearrangement.

Show MeSH